WO2006010642A1 - Derives d'uree cycliques substitues par des heterocycles, preparation et utilisation pharmaceutique de ces derives en tant qu'inhibiteurs de kinases - Google Patents

Derives d'uree cycliques substitues par des heterocycles, preparation et utilisation pharmaceutique de ces derives en tant qu'inhibiteurs de kinases Download PDF

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WO2006010642A1
WO2006010642A1 PCT/EP2005/008721 EP2005008721W WO2006010642A1 WO 2006010642 A1 WO2006010642 A1 WO 2006010642A1 EP 2005008721 W EP2005008721 W EP 2005008721W WO 2006010642 A1 WO2006010642 A1 WO 2006010642A1
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radicals
alkyl
chosen
products
optionally substituted
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PCT/EP2005/008721
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Hartmut Strobel
Sven Ruf
Dominique Lesuisse
Conception Nemecek
Stefan Guessregen
Anne Lebrun
Kurt Ritter
Jean-Luc Malleron
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Aventis Pharma S.A.
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Priority to EP05776537A priority Critical patent/EP1773828A1/fr
Priority to JP2007523039A priority patent/JP2008508229A/ja
Priority to AU2005266461A priority patent/AU2005266461A1/en
Priority to CA002571324A priority patent/CA2571324A1/fr
Priority to BRPI0513863-9A priority patent/BRPI0513863A/pt
Application filed by Aventis Pharma S.A. filed Critical Aventis Pharma S.A.
Priority to EA200700142A priority patent/EA200700142A1/ru
Priority to MX2007000735A priority patent/MX2007000735A/es
Publication of WO2006010642A1 publication Critical patent/WO2006010642A1/fr
Priority to IL180257A priority patent/IL180257A0/en
Priority to US11/627,505 priority patent/US20070259891A1/en
Priority to NO20071073A priority patent/NO20071073L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel cyclic urea, derivatives, to a process for preparing them, to their use as medicinal products, to pharmaceutical compositions containing them and to the pharmaceutical use of such derivatives for preventing and treating complaints that may be modulated by inhibiting the activity of protein kinases.
  • the present invention relates to novel cyclic urea derivatives that have inhibitory effects on protein kinases.
  • the products of the present invention may thus be used especially for preventing or treating complaints capable of being modulated by inhibiting the activity of protein kinases.
  • Such protein kinases belong especially to the following group: IGFl, Raf, EGF, PDGF, VEGF, Tie2, KDR, Fltl-3, FAK, Src, AbI, cKit, cdkl-9, Auroral-2, cdc7, Akt, Pdk, S6K, Jnk, IR, FLK-I, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, PLK, Pyk2, CDK7, CDK2 et EGFR.
  • Such protein kinases belong more especially to . the following group: IGFl, cdc7, Auroral-2, Src, Jnk, FAK, KDR, IR, Tie2, CDK7, CDK2 et EGFR.
  • the protein kinase- IGFl-R Insulin Growth Factor-1 Receptor is particularly indicated.
  • the protein kinase FAK is also indicated.
  • the protein kinase AKT is also indicated.
  • the present invention thus relates particularly to novel inhibitors of the IGF-IR receptor that may be used for oncology treatments.
  • the present invention also relates to novel FAK receptor inhibitors that may be used for oncology treatments.
  • the present invention also relates to novel AKT receptor inhibitors that may be used for oncology treatments.
  • Cancer remains a disease for which the existing treatments are clearly insufficient.
  • Certain protein kinases especially including IGF-IR (Insulin Growth Factor 1 Receptor) , play an important role in many cancers.
  • the inhibition of such protein kinases is potentially important in the chemotherapy of cancers, especially for suppressing the growth or survival of tumours.
  • the present invention thus relates to the identification of novel products that inhibit such protein kinases.
  • Protein kinases participate in signalling events that control the activation, growth and differentiation of cells in response either to extracellular mediators or to changes in the ' environment. In general, these kinases belong to two groups: those that preferentially phosphorylate serine and/or threonine residues and those that preferentially phosphorylate tyrosine residues [S.K. Hanks and T. Hunter, FASEB. J., 1995, 9, pages 576- 596] .
  • the serine/threonine kinases are, for example, the isoforms of the protein- kinases C [A.C. Newton, J. Biol.
  • Tyrosine kinases comprise growth factor receptors, for instance ' the epidermal growth factor (EGF) receptor
  • kinase protein activity has been implicated in many diseases, resulting from abnormal cellular functions. This may arise either directly or indirectly from a dysfunction in the mechanisms for controlling the kinase activity, linked, for example, to a mutation, an overexpression or an inappropriate activation of the enzyme, or an over- or underproduction of cytokines .or of growth factors, also involved in the transduction of the signals upstream or downstream of the kinases. In all these cases, a selective inhibition of the action of the kinases offers hope of a beneficial effect.
  • the type 1 receptor for the insulin-like growth factor is a transmembrane receptor with tyrosine kinase activity, which binds firstly to IGFI, but also to IGFII and to insulin with lower affinity.
  • the binding of IGFl to its receptor results in oligomerization of the receptor, the activation of tyrosine kinase, intermolecular autophosphorylation and the phosphorylation of cell substrates (main substrates: IRSl and She) .
  • the receptor activated by its ligand induces mitogenic activity in normal cells-.
  • IGF-I-R plays an important role in "abnormal" growth.
  • IGF-I-R is often found overexpressed in many types of tumour (breast, colon, lung, sarcoma, etc.) and its presence is often associated with a more aggressive phenotype.
  • High concentrations of circulating IGFl are strongly correlated with a risk of prostate cancer, lung cancer and breast cancer.
  • IGF-I-R is necessary for establishing and maintaining the transformed phenotype in vitro as in vivo [Baserga R, Exp. Cell. Res., 1999, 253, pages 1-6] .
  • the kinase activity of IGF-I-R is essential for the transformation ' activity of several oncogenes: EGFR, PDGFR, the large T antigen of the SV40 virus, activated Ras, Raf, and v-Src.
  • the expression of IGF-I-R in normal fibroblasts induces a neoplastic phenotype, which may then result in the formation of a tumour in vivo.
  • the expression of IGF-I-R plays an important role in substrate-independent growth.
  • IGF-I-R has also been shown to be a protector in chemotherapy-induced and radiation-induced apoptosis, and cytokine-induced apoptosis. Furthermore, the inhibition of endogenous IGF-I-R with a negative dominant, the formation of a triple helix or the expression of an ' antisense sequence brings about suppression of the transforming activity in vitro and reduction of tumour growth in 'animal models.
  • kinases for which a modulation of the • activity is desired FAK (Focal Adhesion Kinase) is also a preferred kinase.
  • FAK is a cytoplasmic tyrosine kinase that plays an important role in transducing the signal transmitted by the integrins, a family of heterodimeric receptors of cellular adhesion.
  • FAK and the integrins are colocalized in perimembrane structures known as adhesion plaques. It has been shown in many cell types that the activation of FAK and its phosphorylation on tyrosine residues and in particular its autophosphorylation on tyrosine 397 were dependent on the binding of the integrins to their extracellular ligands and thus induced during cellular adhesion [Kornberg L, et al. J. Biol. Chem.
  • the autophosphorylation on tyrosine 397 of FAK represents a binding site for another tyrosine kinase, Src, via its SH2 domain [Schaller et al. MoI. Cell. Biol. 14: 1680-1688 1994; Xing et al. MoI. Cell. Biol. 5: 413-421 1994].
  • Src can then phosphorylate FAK on tyrosine 925, thus ⁇ • recruiting the adapter protein Grb2 and inducing in certain cells activation of the ras and MAP kinase pathway involved in controlling cellular proliferation [Schlaepfer et al.
  • PI3-kinase Phosphatidylinositol-3-OH kinase
  • Pl3-kinase also binds to FAK on tyrosine 397 and this interaction might be necessary for the activation of Pl3-kinase [Chen and Guan, Proc. Nat. Acad. Sci. USA. 91: 10148-10152 1994; Ling et al. J. Cell. Biochem.
  • the FAK/Src complex phosphorylates various substrates, for instance paxillin and pl30CAS in fibroblasts [Vuori et al. MoI. Cell. Biol. 16: 2606-2613 1996] .
  • fibroblasts that are deficient for the expression of FAK show a rounded morphology and deficiencies in cell migration in response to chemotactic signals, and these defects are suppressed by reexpression of FAK [DJ. Sieg et al., J. Cell Science. 112: 2677-91 1999] .
  • the overexpression of the C-terminal domain of FAK (FRNK) blocks the stretching of adherent cells and reduces cellular migration in vitro [Richardson A. and Parsons J.T. Nature. 380: 538-540 1996].
  • the overexpression of FAK in CHO or COS cells or in human astrocytoma cells promotes migration of the cells.
  • Protein kinase AKT also known as PKB
  • PI3K phosphoinositide 3-kinase
  • AKT serine/threonine kinase
  • BAD BAD
  • GSK3D caspase-9
  • Fprkhead transcription factor ' can activate IKKalpha . and e-NOS.
  • the protein BAD is found hyper-phosphorylated in 11 human tumour cell lines out' of 41 studied.
  • hypoxia modulates the induction of VEGF in cells transformed with Ha-ras by activating the PI3K/AKT pathway and by involving the binding sequence of the HIF-I (hypoxia inducible factor-1) transcription factor known as HRE for "hypoxy-responsive element".
  • HIF-I hypoxia inducible factor-1 transcription factor known as HRE for "hypoxy-responsive element".
  • AKT plays a very important role in cancer pathologies. The amplification and/or overexpressi ' on of AKT has been reported in.
  • AKT is constitutively activated in all the PTEN (-/-) tumours, the PTEN phosphatase being deleted or - inactiyated by mutations in many types of tumours, for instance carcinomas of the ovary, of the prostate, of the endometrium, glioblastomas and melanomas.
  • AKT is also involved in the oncogenic activation of bcr-abl
  • V represents an unsaturated or partially or totally saturated monocyclic or bicyclic heterocyclic 5- to 11- membered radical, containing one or more other hetero atoms, which may be identical or different, chosen from O, N, NR4 and S, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of Y and Yl; the atom S that V can contain, being optionally oxidized by one or two oxygen,
  • Yo, Y and Yl which may be identical or different, are such that Yo represents hydrogen or alkyl and one from among Y and Yl is chosen from OCF3; -O-CF2-CHF2; -O-CHF2; -O-CH2-CF3; -SO2NR5R6; SF5; -S (O) n-alkyl; alkyl containing 1 to 7 carbon atoms optionally substituted with one or more fluorine atoms or cycloalkyl radicals; 3- to 7-membered cycloalkyl optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms and alkyl radicals containing 1 to 3 carbon atoms; alkylamino, optionally substituted with one or more flourine atoms; dialkylamino, optionally substituted with one or more radicals, ' which may be identical or different, .
  • a 4- to 10- membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, NR4 and S and optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; phenyl, phenoxy; arylmercapto or heteroarylmercapto, optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms and alkyl and alkoxy radicals; and the other from among Y and Yl is chosen from these same values and in addition from the following values: hydrogen; halogen; hydroxyl; oxo; acyl; alkoxy; nitro; CN; NR5R6; optionally substituted alkyl; optionally substituted aryl and
  • Rl represents 0 or NH
  • R2, -R2', R3 and R3' which may be identical or different, represent hydrogen, halogen; alkyl, alkenyl, alkynyl, cycloalkyl, cycloal ' kylalkyl, aryl and heteroaryl, all optionally substituted, or alternatively two of the residues R2, R2', R3 and R3' form, together with the carbon atoit ⁇ (s) to which they are attached, a carbocyclic or heterocyclic radical, these radicals being 3- to 10- merabered and the heterocyclic radical containing one or more hetero atoms chosen from 0, S, N and NR4, all these radicals optionally being substituted;
  • A represents a single bond; an alkylene radical; an alkenyl radical; alkynyl; CO; S02; 0; NH; NH-alkyl;
  • B represents a saturated or unsaturated monocyclic or bicyclic heterocyclic radical containing one or more hetero atoms, which may be identical or different, chosen from 0, S, N and NR4, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of Y2;
  • Y2 represents hydrogen; halogen; hydroxyl; cyano; alkyl; alkoxy; cycloalkyl; heterocycloalkyl; aryl; heteroaryl;
  • R4 represents a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, alkylCO, alkylSO 2 , or aryle radical, all optionally substituted with one or more substituents, . which may be identical or different, chosen from halogen . atoms; hydroxyl; alkoxy; dialkylamino; aryl and heteroaryl radicals, these last two radicals optionally substituted with one or more substituents, which may be.
  • R5 and- R6, which may be identical or different, are chosen ' from hydrogen; alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, all optionally -substituted or alternatively R5 and R6 form, with the nitrogen atom to which they are attached, a 3- to 10-membered heterocyclic radical containing one or more hetero atoms chosen from O, S, N and optionally substituted NR4; all the above alkyl, alkenyl, alkynyl and alkoxy radicals being linear or branched and containing up to 6 carbon atoms; all the above cycloalkyl and heterocycloalkyl radicals containing up to 7 carbon atoms; all the above aryl and heteroaryl radicals containing up to 10 carbon atoms; all the above alkyl, alken
  • R8 represents alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkyl- alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; all these radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cyano, hydroxyl, alkoxy, alkyl, CF3, nitro, phenyl and free, salified, esterified or amidated carboxyl radicals; R9 represents the values of R8 and hydrogen; RlO represents hydrogen or alkyl;
  • RlI • and R12 which may be identical or different, represent hydrogen; alkyl, cycloalkyl and phenyl optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cyano, hydroxyl, alkoxy, alkyl, CF3, nitro, phenyl and free, salified, esterified or amidated carboxyl radicals; or alternatively RlI and R12 form, with the nitrogen atom to which they are attached, a 5- to 7-membered cyclic radical containing one or more hetero atoms chosen from 0, S, N and NR14 and preferably a cyclic amine, ⁇ optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cyano f hydroxyl, alkoxy, alkyl, CF3, nitro, phenyl, phenylalkyl and free, salified, esterified or amidated carboxyl- radicals; Rl3,
  • V represents an unsaturated or partially or totally saturated monocyclic or bicyclic heterocyclic 5- to 11-membered radical, containing one or more other hetero atoms, which may be identical or different, chosen from 0, N, NR4 and S, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of Y and Yl; Y and Yl, which may be identical or different, are such that one from among Y and Yl is chosen from OCF3; -O-CF2- CHF2; -0-CHF2; -O-CH2-CF3; -SO2NR5R6; SF5; -S (0)n-alkyl; alkyl containing 1 to 7 carbon atoms optionally substituted with one or more- fluorine atoms or cy.clalkyl radicals; 3- to 7-membered cycloalkyl optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms and al
  • A represents a single bond; an alkylene radical; an alkenyl radical; alkynyl; CO; SO2; 0; NH; NH-alkyl;
  • B represents a saturated or unsaturated monocyclic or bicyclic heterocyclic radical containing one or more hetero atoms, which may be identical or different, chosen from O, S, N and NR4, optionally substituted with one or more substituents, which may be identical or different, chosen from the values of Y2;
  • Y2 represents hydrogen; halogen; hydroxyl; cyano; alkyl; alkoxy; cycloalkyl; heterocycloalkyl; aryl; heteroaryl;
  • R4 represents a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl, alkylCO, alkylSO 2 , or aryle radical, all optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms; hydroxyl; alkoxy; dialkylamino; aryl and heteroaryl radicals, these last two radicals optionally substituted with one or more substituents, which may be identical or different, chosen from halogen atoms and alkyl and alkoxy radicals; R5 and R6, which may be identical or different, are chosen from hydrogen; alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, optionally substituted aryl and heteroaryl; or alternatively R5 and R6 form, with the nitrogen atom to which they are attached, a 3- to 10-membered heterocyclic radical containing one or more hetero atoms
  • N(RlO) -C ( O)-NR11R12; -N (RlO) -S (0) n-R8; -S(0)n-R8; -N(RlO) -S (O)n-NR11R12 and -S (0)n-NRllRl2 radicals; all the above aryl and heteroaryl radicals also being • optionally substituted with one or more radicals chosen from alkyl, phenylalkyl, alkoxy and alkylenedioxy radicals;all the above cyclic radicals and also the ring formed by R5 and R6 with the atom to which they are attached being also optionally substituted with one or more radicals chosen from oxo and thioxo; n represents an integer from 0 to 2,
  • R8 represents alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkyl- alkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; all these radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cyano, hydroxyl, alkoxy, alkyl, CF3, nitro, phenyl and free, salified, esterified or amidated carboxyl radicals;
  • R9 represents the values of R8 and hydrogen
  • RlO represents hydrogen or alkyl
  • RlI and R12 which may be identical or different, represent hydrogen; alkyl, cycloalkyl and phenyl optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cyano, hydroxyl, alkoxy, alkyl, CF3, nitro, phenyl and free, salified, esterified or amidated carboxyl radicals; or alternatively RlI and R12 form, with the nitrogen atom to which they are attached, a 5- to 7 ⁇ membered cyclic radical containing one or more hetero atoms chosen from O, S, N and NR14 ⁇ and preferably a cyclic amine, optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cyano, hydroxyl, alkoxy, alkyl, CF3, nitro, phenyl, phenylalkyl and free, salified, esterified or amidated carboxyl radicals;
  • R13 which may be identical to or different from R5 or
  • R ⁇ being chosen from the values of R5 or R ⁇ ; the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I) .
  • a subject of the present invention is, more specifically, the products of formula (I) as defined above corresponding to formula (Ia) :
  • Va represents a 5- or ⁇ -membered heteroaryl radical or a 9- to 11-membered fused heterocyclic radical, containing one or more other hetero atoms, which may be identical or different, chosen from O, N, NR4a and S; optionally substituted with one or more substituents, which, may be identical or different, chosen from the values of Ya and YIa;
  • Ya and YIa which may be identical or different, are such that one from among Ya and YIa is chosen from OCF3; -0- CF2-CHF2; • -O-CHF2; -O-CH2-CF3; SO2NR5aR6a; SF5; -S(O)n- alkyl; alkyl containing 1 to 7 carbon atoms optionally substituted with one or more fluorine atoms; 3- to 7- membered cycloalkyl optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms , alkyl radicals containing 1 to 3 carbon atoms, cyclopropyl; alkylamino, optionally substituted with one or more fluorine atoms; dialkylamino, optionally substituted with one or more radicals, which may be identical or different, chosen from fluorine atoms and alkoxy radicals and in which the two alkyl residues may optionally form, together with the nitrogen
  • RIa stands for 0
  • R2a, R2a' , R3a, R3a' represent hydrogen and alkyl, it being understood that two of the substituents R2a, R2a' , R3a, R3a' can . form, together with the carbon atom to which they are attached, a 3- to 6-membered cycloalkyl or heterocycloalkyl radical containing a nitrogen atom, all these radicals being optionally substituted;
  • Aa represents a single bond; an alkylene radical; CO; S02; 0; NH; NH-alkyl;
  • Ba represents pyridyl, pyrimidinyl, quinolyl, azaindolyl, quinazolyl, thiazolyl, imidazolyl, pyrazolyl, furazanyl, isoxazolyl, morpholinyl, pyrrolidinyl, furyl, piperidyl, thienyl, chromenyl, oxochromenyl, indolyl, pyrrolyl, purinyl, benzoxazinyl, benzimidazolyl, indazolyl and benzofuryl radicals, these radicals being optionally substituted with one or more radicals chosen from the values of Y2a;
  • Y2a represents hydrogen; halogen; hydroxyl; alkyl; alkoxy; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; 0-allyl; 0-propynyl; O-cycloalkyl; S(O)n-alkyl; S(0)n- allyl; S (0)n-propynyl; S (0) n-cycloalkyl; C00R9a; 0C0R8a; NR5aR ⁇ a; CONR5aR6a; S (0) n-R5aR ⁇ a; NHCOR8a; -NRlOa-CO- NR5aR ⁇ a NH-S(0)nR8a; NH-S(0)nCF3; NH-S02-NR5aR6a, all these radicals being optionally substituted;
  • R4a represents a hydrogen atom; an alkyl; cycloalkyl; or phenyl, all optionally substituted;
  • R5a and R ⁇ a which may be identical or different, are chosen from hydrogen, . alkyl, alkenyl, cycloaikyl, cycloalkenyl, heterocycloalkyl, optionally substituted aryl and heteroaryl; or alternatively R5a and R6a form, with the nitrogen atom to which they are attached, a 3- to 10-membered heterocyclic radical containing one or more hetero atoms chosen from 0, S, N and optionally substituted NR4a; all the above alkyl, alkenyl, alkynyl and alkoxy radicals being linear or branched and containing up to 6 carbon atoms; all the above cycloalkyl and heterocycloalkyl radicals containing up to 7 carbon atoms, all the above aryl and heteroaryl radicals containing up to 10 carbon atoms; all the above alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl
  • R8a represents alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkyl- alkyl, phenyl, phenylalkyl, heteroaryl and heteroarylalkyl; all these radicals being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and hydroxyl, alkoxy, alkyl, CF3, nitro, phenyl and free, salified, esterified or amidated carboxyl radicals;
  • R9a represents the values of R8 and hydrogen;
  • RlOa represents hydrogen or alkyl;
  • RlIa and R12a which may be identical or different, represent hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl and phenylalkyl optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cyano, hydroxyl, alkoxy, alkyl, CF3, nitro, phenyl and free, salified, esterified or amidated carboxyl radicals; or alternatively RlIa and R12a form, with the nitrogen atom to which they are attached, a cyclic radical chosen from pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, indolinyl, pyrindolinyl, tetrahydroquinolyl, thiazolidinyl ' and naphthyridyl; optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and alkyl, phen
  • alkyl radicals containing up to 6 carbon atoms and especially methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, linear or branched pentyl and linear or branched hexyl radicals.
  • alkenyl radical denotes a linear or branched radical containing up to 12 carbon atoms and preferably 4 carbon atoms, chosen, for example, from the following values: ethenyl or vinyl, propenyl or allyl, 1-propenyl, n-butenyl, i-butenyl, 3-methyl-2-butenyl, n-pentenyl, hexenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl, and also the linear or branched positional isomers thereof.
  • alkenyl values that may be mentioned more particularly are the values allyl or butenyl.
  • alkynyl radical denotes a linear or branched radical containing up to 12 carbon atoms and preferably 4 carbon atoms, chosen, for example, from the following values: ethynyl, propynyl or propargyl, butynyl, n- butynyl, i-butynyl, 3-methyl-2-butynyl, pentynyl or hexynyl, and also the linear or branched positional isomers thereof.
  • alkynyl values that are mentioned more particularly is the propargyl value.
  • alkoxy radical denotes a linear or branched radical containing up to 12 carbon atoms and preferably 6 carbon atoms chosen, for example, from methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy, hexoxy and heptoxy radicals, and also the linear or branched positional isomers thereof
  • alkoxycarbonyl radical or alkyl-O-CO- denotes a linear or branched radical containing up to 12 carbon atoms, in which the alkyl radical has the meaning given above: examples that may be mentioned include methoxycarbonyl and ethoxycarbonyl radicals
  • alkylenedioxy radical or -0-alkylene-O- denotes a linear or branched radical containing up to 12 carbon atoms, in which the alkylene radical has the meaning
  • alkylsulfinyl or alkyl-SO- denotes a linear or branched radical containing up to 12 carbon atoms, in which the alkyl radical has the meaning given above and preferably contains 4 carbon atoms,
  • alkylsulfonyl or alkyl-SO2- denotes a linear or branched radical containing up to 12 carbon atoms, in which the alkyl radical has the meaning given above and preferably contains 4 carbon atoms
  • alkylthio or alkyl-S- denotes a linear or branched radical containing up to 12 carbon atoms and especially ⁇ represents methylthio, ethylthio, isopropylthio and heptylthio radicals
  • cycloalkyl radical denotes a 3- to. 10- membered monocyclic or bicyclic carbocyclic radical and especially denotes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals,
  • -O-cycloalkyl radical denotes a radical in which the cycloalkyl radical has the meaning given above
  • cycloalkenyl radical denotes a 3- to 10- membered monocyclic or bicyclic nonaromatic carbocyclic radical containing at least one double bond, and especially denotes cyclobutenyl, cyclopentenyl and cycl ⁇ hexenyl radicals,
  • cycloalkylalkyl radical denotes a radical in which cycloalkyl and alkyl are chosen from the values indicated above: this radical thus denotes, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl radicals,
  • acyl radical or r-CO- denotes a linear or branched radical containing up to 12 carbon atoms, in which the radical r represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkenyl, cycloalkyl, heterocycloalkyl or aryl radical, these radicals having the values indicated above and being optionally substituted as indicated: examples that are mentioned include the formyly acetyl, propionyl, butyryl or benzoyl radicals, or alternatively " valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl,
  • acyloxy radical means acyl-0- radicals in which acyl has the meaning given above: examples that are mentioned include acetoxy or propionyloxy radicals, - the term “acylamino radical” means acyl-NH- radicals in which acyl has the meaning given above,
  • aryl radical denotes unsaturated monocyclic radicals or unsaturated radicals consisting of fused carbocyclic rings. Examples of such aryl radicals that may be mentioned include phenyl or naphthyl radicals.
  • arylalkyl means radicals resulting from the combination of the optionally substituted alkyl radicals mentioned above and the optionally substituted aryl radicals also mentioned above: examples that are mentioned include benzyl, phenylethyl, 2-phenethyl, triphenylmethyl or naphthalenemethyl radicals, the term “heterocyclic radical” denotes a saturated carbocyclic radical (heterocycloalkyl) or unsaturated carbocyclic radical (heteroaryl) which is at most ⁇ -membered, interrupted with one or more hetero atoms, which may be identical or different, chosen from oxygen, nitrogen and sulfur atoms.
  • Heterocycloalkyl radicals that may especially be mentioned include dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, piperidyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, morpholinyl, or tetrahydrofuryl, tetrahydrothienyl, chromanyl, dihydrobenzofuranyl, indolinyl, piperidyl, perhydropyranyl, pyrindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and thioazolidinyl radicals, all , these radicals being optionally substituted.
  • heterocycloalkyl radicals that may especially be mentioned are optionally substituted piperazinyl, optionally substituted piperidyl, optionally substituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl and thioazolidinyl radicals: mention may also be made more particularly of optionally substituted morpholinyl, pyrrolidyl and piperazinyl radicals;
  • heterocycloalkylalkyl radical means radicals in which the heterocycloalkyl and alkyl residues have the above .meanings;
  • furyl radicals such as 2-fury1, thienyl radicals such as 2-thienyl and 3-thienyl, and pyrrolyl, diazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, isothiazolyl, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl, imidazolyl, pyrazolyl and isoxazolyl radicals.
  • furyl radicals such as 2-fury1, thienyl radicals such as 2-thienyl and 3-thienyl
  • pyrrolyl diazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, isothiazolyl, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl, imidazolyl, pyrazolyl and isoxazolyl radicals.
  • 6-membered heteroaryl radicals such as 2-pyridyl, 3-pyridyl and 4-pyridyl, and pyrimidyl, pyrimidinyl, pyridazinyl, pyrazinyl and tetrazolyl radicals; - as fused heteroaryl radicals containing at least one hetero atom chosen from sulfur, nitrogen and oxygen, examples that •may be mentioned include benzothienyl such as 3-benzothienyl, benzofuryl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzoxaz ⁇ lyl, thionaphthyl, indolyl, purinyl, quinolyl, isoquinolyl and naphthyridinyl.
  • pyridyl radicals such as 2-pyridyl, 3-pyridyl and 4-pyridyl, and pyrimidyl, pyrimidinyl, pyridaziny
  • fused heteroaryl radicals that may be mentioned more particularly are- benzothienyl, benzofuranyl, indolyl, quinolyl, benzimidazolyl, benzothiazolyl, furyl, imidazolyl, indolizinyl, isoxazolyl, isoquinolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl,- pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, 1.3.4-thiadiazolyl, thiazolyl and thienyl radicals and triazolyl groups, these radicals optionally being substituted as indicated for the heteroaryl radicals; - the term "cyclic amine” denotes a 3- to 8-membered cycloalkyl radical in which one carbon atom is replaced with a nitrogen atom, the cycloalkyl radical having the meaning given
  • patient denotes human beings, but also other mammals.
  • prodrug denotes a product that may be converted in vivo via metabolic mechanisms (such as hydrolysis) into a product of formula (I) .
  • metabolic mechanisms such as hydrolysis
  • an ester of a product of formula (I) containing a hydroxyl group may be converted by hydrolysis in vivo into its parent molecule.
  • an ester of a product of formula (I) containing a carboxyl group may be converted by in vivo hydrolysis into its parent molecule.
  • esters of the products of formula (I) containing a hydroxyl group include the acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylenebis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-tolyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.
  • Esters of products of formula (I) that are particularly- useful, containing a hydroxyl group may be prepared from acid residues such as those described by Bundgaard et. al., J. Med. Chem. , 1989, 32, page 2503-2507: these esters especially include substituted (aminomethyl)benzoates, dialkylaminomethylbenzoates in which the two alkyl groups may be linked together or may be interrupted with an oxygen atom or with an optionally substituted nitrogen atom, i.e. an alkylated nitrogen atom, or alternatively (morpholinomethyl)benzoates, eg. 3- or 4- (morpholinomethyl)benzoates, and (4-alkyl- piperazin-1-yl)benzoates, eg.
  • the carboxyl radical (s) of the products of formula (I) may be salified or esterified with various groups known to those skilled in the art, among which nonlimiting examples that may be mentioned include the following compounds:
  • mineral bases such as, for example, one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium
  • organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N- dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methylglucamine,
  • alkyl radicals to form alkoxycarbonyl groups such as, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxy.carbonyl or benzyloxycarbonyl, these alkyl radicals possibly being substituted with radicals chosen, for example, from halogen atoms and hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals, such as, for example, in chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.
  • esterified carboxyl means, for example, radicals such as alkyloxycarbonyl radicals, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl.
  • radicals formed with readily cleavable ester residues such as methoxymethyl or ethoxymethyl radicals; acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; alkyloxycarbonyloxyalkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, and isopropyloxycarbonyloxy methyl or ethyl radicals.
  • ester radicals may be found, for example, in European patent EP 0 034 536.
  • aminodated carboxyl means radicals of the type -CONR5R6 as defined above.
  • alkylamino radical means linear or branched methylamino, ethylamino, propylamino or butylamino radicals. Alkyl radicals containing up to 4 carbon atoms are preferred, the alkyl radicals possibly being chosen from the alkyl radicals mentioned above.
  • dialkylamino radical means, for example, dimethylamino, diethylamino and methylethylamino radicals. As previously, alkyl radicals containing up to 4 carbon atoms, chosen from the list indicated above, are preferred.
  • the radicals NR5R6 or NR11R12 may also represent a heterocycle which may or may not comprise an additional hetero atom. Mention may be made of pyrrolyl, imidazolyl, indolyl, piperidyl, pyrrolidinyl, morpholinyl and piperazinyl radicals. The piperidyl, pyrrolidinyl, morpholinyl and piperazinyl radicals are preferred.
  • salts formed for example, with one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Mention may also be made of the salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine and triethylamine. The sodium salt is preferred.
  • the addition salts with mineral or organic acids of the products of formula (I) may be, for example, the salts formed with hydrochloric acid, hydrobromic acid, hydriodic acid, nitric acid, sulfuric acid, phosphoric acid, propionic acid, acetic acid, trifluoroacetic acid, formic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid, alkylmonosulfonic acids such as, for example, methanesulfonic acid, ethanesulfonic acid or propanesulfonic acid, alkyldisulfonic acids such as, for example, methanedisulfonic acid or alpha,beta- ethanedisulfonic acid, arylmonosulfonic acids such as benzenesulfonic acid, and aryldisulfonic acids.
  • stereoisomerism may be defined in its broad sense as the isomerism of compounds having the same structural formulae but whose various groups are arranged differently in space, especially such as in monosubstituted cyclohexanes whose substituent may be in
  • stereoisomerism due to the different spatial arrangements of fixed substituents, either on double bonds or on rings, which is often referred to as geometrical isomerism or cis-trans isomerism.
  • the term "stereoisomer" is used in the present patent application in its broadest sense and thus relates to all the compounds indicated above.
  • a subject of the invention is especially the products of formula (I) as defined above, such that p represents the integer 0, the other substituents of the said products of formula (I) having any one of the values defined above.
  • a subject of the invention is especially the products of formula (I) as defined above, such that p represents the integer 1, the other substituents of the said products of formula (I) having any one of the values defined above.
  • a subject of the invention • is especially the products of formula (I) as defined above, such that p represents the integer 2, the other substituents of the said products of formula (I) having the values defined in the present invention.
  • a subject of the present invention is especially the. products- of formula (I) or (Ia) as defined above corresponding to formula (Ib) :
  • Vb represents pyridine; pyrimidine; pyrrole; thiophene; thiazole; imidazole; oxazole; pyrazole; isoxaozole; indole; indazole; benzimidazole; benzothiazole; benzoxazole; 2, 3-dihydro-lH-indole; 2, 3-dihydro-lH- isoindole; 2, 3-dihydrobenzothiazole; 1,2, 3, 4-tetrahydro- quinoline, 1, 2, 3, 4-Tetrahydro-isoquinoline, triazole; oxadiazole; dihydrobenzothiazine; benzodioxinyl; benzopyranyl; quinolyl; optionally substituted with one or more substituents, which may be identical or different, chosen from the values of Yb and YIb;
  • Yb and YIb which may be identical or different, are such that one from among Yb and YIb is chosen from OCF3; S(O)nCF3; S(O)nAlk; SO2CHF2; SO2CF2CF3; SO2NR5bR ⁇ b; alkyl containing 1 to 6 carbon atoms optionally substituted by one or more F; 3- to 6-membered cycloalkyl optionally substituted with one or more methyl radicals or one or more F; alkylamino; dialkylamino, in which the two alkyl residues may optionally form, together with the nitrogen atom to which they are attached, a 5- or ⁇ -membered heterocycle optionally containing one or more other hetero atoms, which may be identical or different, chosen from O, N, Nalkyl and S and optionally substituted with one.
  • radicals which may be identical or different, chosen from fluorine atoms and alkyl radicals; phenyl, phenoxy; 5- to ⁇ -membered phenylmercapto or heteroarylmercapto, optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and alkyl radicals; and the other from among Yb and YIb is chosen from the same values and also from hydrogen; halogen; hydroxyl; oxo; nitro; free or esterified carboxyl; NR5bR6b; optionally substituted alkyl, alkoxy and phenyl; -O-CF2- CHF2; -O-CHF2; -O-CH2-CF3; -S-CF2-CF2-CF3; - -S-AIk-O- AIk; -S-AIk-OH; -S-AIk-CN; -S-Alk-heterocycloalkyl; pyr
  • R2b and R2b' represent hydrogen and alkyl, or two substituents R2b and R2b' , can form, together with the carbon atom to which they are attached, a cycloalkyl radical containing from 3 to 6 carbon atoms, or form an azetidinyl, pyrrolidinyl or piperidyl radical.
  • Ab represents a single bond, an alkylene radical;; 0; NH; NH-alkyl;
  • Bb represents a heterocyclic radical chosen from 3- or 4- pyridyl; pyrimidinyl; ; 3- or 4- quinolyl; azaindolyl; quinazolyl;indazolyl; thiazolyl; imidazolyl; pyrazolyl, furazanyl and isoxazolyl radicals; these radicals being optionally substituted with one or more radicals chosen from the values of Yb, Y2b represents hydrogen; halogen; hydroxyl; alkyl; alkoxy; cycloalkyl; heterocycloalkyl; phenyl; heteroaryl; 0-cycloalkyl; S-(O) n-alk; S (O)n-cycloalkyl; COOR9; _.
  • R4b represents a hydrogen atom or an alkyl, cycloalkyl or phenyl radical
  • R5b and R6b which may be identical or different, are chosen from hydrogen, alkyl, -alkenyl, cycloalkyl, heterocycloalkyl, optionally substituted phenyl and heteroaryl or alternatively R5b and R6b form, with the nitrogen atom to which they are attached, a 3- to 10- membered heterocyclic radical containing one or more hetero atoms chosen from O, S, N and optionally substituted NR4b, all the above alkyl, alkenyl, alkynyl and alkoxy radicals being linear or branched and containing up to 6 carbon atoms, all the above cycloalkyl and heterocycloalkyl radicals containing up to 7 carbon atoms, all the above aryl and heteroaryl radicals containing up to 10 carbon atoms, all the above radicals being optionally substituted with one or more radicals chosen from halogen, cyano, hydroxyl, alkyl and alkoxy containing 1 to 4 carbon atoms,
  • R8b represents alkyl, cycloalkyl, cycloalkylalkyl and phenyl, '
  • R9b which may be identical to or different from R8b, represents hydrogen and the values of R8b, RlIb ' and R12b, which may- be identical or different, represent hydrogen, alkyl, cycloalkyl and phenyl or alternatively RlIb and Rl2b form, with the nitrogen atom to which they are attached, a pyrolidine, piperidinyl, morpholinyl or a piperazinyl radical optionally substituted with an alkyl, phenyl or phenylalkyl radical; the said products of formula (Ib) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and - organic acids or with mineral and organic bases of the said products of formula (Ib) .
  • a subject of the present invention is especially the products of formula (I) , (Ia) or (Ib) as defined above corresponding to formula (Ic) :
  • Vc represents pyrrole, thiophene, thiazole, pyrazole, , indazole, 2, 3-dihydro-lH-indole: benzodioxinyl ; benzopyranyl ; optionally substituted with one or more substituents, which, may be identical or . different, chosen from the values of Yc and YIc;
  • Yc and YIc which may be identical or different, are such that one from among Yc and YIc is chosen from OCF3; -S(O)nCF3; S (0) n-Alk; SO2CHF2; SO2CF2CF3; SO2NR5cR6c; alkyl especially such as methyl, ethyl, isopropyl, tert- butyl, sec-butyl, 1, 2-dimethylpropyl, 1, 1-dimethylpropyl; cyclopropyl or cyclobutyl especially such as 1-methyl- cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclo- propyl, cyclobutyl, 2, 2, 3, 3-tetrafluorocyclobutyl; di (C2-C4-alkyl) amino; piperid-1-yl, thiomorpholin-4-yl, inorpholin-4-yl, pyrrolidin-1-yl optionally substituted with
  • Ac represents a single bond , -0- or -CH2;
  • Bc represents a heterocyclic radical chosen from 3- or 4- pyridyl, pyrimidinyl, , 3- or 4- quinolyl, azaindolyl and quinazolyl, • indazolyl, these radicals being optionally substituted with one or more radicals chosen from the values of Y2c;
  • Y2c represents hydrogen; halogen; alkyl; cycloalkyl; hydroxyl; alkoxy; ; NH2; NHaIk; N(alk)2; NH-Phenyl-; NH-
  • Heteroaryl NH-C0-R5c; NH-CO-heteroaryl; NH-CO-NR5cR6c; and phenyl; all the alkyl, alkoxy phenyl and heteroaryl radicals being optionally substituted;
  • R5c and R6c which may be identical or different, represent hydrogen, alkyl, cycloalkyl and phenyl, which are optionally substituted, or alternatively R5c and R ⁇ c form, with the nitrogen atom to which they are attached, a cyclic radical chosen from pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, piperazinyl, indolinyl, pyrindolinyl, tetrahydroquinoline and azetidine radicals, all these radicals being optionally substituted with one or more radicals chosen from alkyl, alkoxy and phenyl; all the above alkyl, alkoxy and phenyl radicals being optionally substituted with one or more radicals chosen from halogen, OH, alk, OaIk, OCF3, S(O)n-CF3, CF3, NH2, NHAIk and N (alk) 2; it beeing understood, that all dialkylamino radicals optionally
  • R ⁇ c which may be identical or different, represent hydrogen, alkyl, cycloalkyl and phenyl, the alkyl and phenyl radicals being optionally substituted, or alternatively R5c and R ⁇ c form, with the nitrogen atom to which they are attached, a cyclic radical chosen from pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, piperazinyl and azetidine.
  • Bc represents a heterocyclic radical chosen from 3- or 4-pyridyl, IH-pyrrolo [2, 3-b]pyridin-4- yl pyrimidinyl and 3- or 4-quinolyl.
  • Bc represents 4-pyridyl and 4-quinolyl radicals, optionally substituted with one or more radicals chosen from the values of Y2c,
  • a subject of the present invention is especially the products of formula (I) as defined above corresponding to formula (Id) :
  • Vd represents pyridine; pyrimidine; pyrrole; thiophene; thiazole; imidazole; oxazole; pyrazole; isoxaozole;; indazole; benzimidazole; benzothiazole; benzoxazole; 2,3- dihydro-lH-indole; 2, 3-dihydro-lH-isoindole; 2,3- dihydrobenzothiazole; triazole; oxadiazole; dihydrobenzothiazine; benzodioxinyl; benzopyranyl; quinolyl;
  • Yd and YId which may be identical or different, are such that one from among Y and Yl is chosen from alkyl, optionally substituted by one or more fluorine atoms, phenyl, O-phenyl, S(O)n-alkyl, S (0) n-alkylphenyl and morpholino and one or and the other from among Y and Yl is chosen from these same values and in addition from the following values: F, Cl and Br atoms; hydroxyl; oxo; cyan ⁇ ; free or esterified carboxyl; COCH3; phenyl; O- phenyl; S(O)n alkyl; S (0) n-alkylphenyl and morpholino ⁇ radicals; all the alkyl and phenyl radicals being themselves optionally substituted with one or more radicals , which- may be identical or different, chosen from halogen atoms and alkyl, alkoxy, OCF3, cyano, amino, al
  • Ad represents a single bond or CH2
  • Bd represents a quinolyl or pyridyl radical optionally substituted with one or more radicals Y2d chosen from halogen, -OH, alk, -OaIk, -C02H, -CO2alk, -NH2, NHaIk, N(alk)2, -CF3, -OCF3 and phenyl,NH-phenyl; NH-heteroaryl NH-CO-phenyl, NH-CO-heteroaryl; NH-CO-NH-alkyl; NH-CO-NH- dialkyl ; NH-CO-NH-phenyl;the alkyl and phenyl radicals being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl and alkoxy and dialkylamino radicals; it beeing understood, that all • dialkylamino radicals optionally can form a pyrrolidine, piperidine, morpholine or piperazine ring optionally
  • V represents pyridine; pyrimidine; pyrrole; thiophene; thiazole; dithiazole; imidazole; oxazole; isoxazole; pyrazole; isoxaozole; indazole; benzimidazole; benzothiazole; benzoxazole; 2, 3-dihydro-lH-indole; 2,3- dihydro-lH-isoindole; 2, 3-dihydrobenzothiazole; triazole; oxadiazole; dihydrobenzothiazine; benzodioxinyl; benzopyranyl; quinolyl; 1,2,3,4 tetrahydroquinolyl; the atom S that V can contain, being optionally oxidized by one or two oxygen,
  • Yo, Y and Yl which may be identical or different, are such that Yo represents hydrogen or alkyl and one from among Y and Yl is chosen from alkyl optionally substituted by one or more fluorine atoms, phenyl, 0- phenyl, S (0) n-alkyl> S (0) n-alkylphenyl and morpholino and the other from among Y and Yl is chosen from these same values and in addition from the following values: F, Cl and Br atoms; hydroxyl; oxo; cyano; free or esterified carboxyl; C0CH3; -alkyl-CO-piperazinyl itself optionally substituted by alkyl; phenyl; 0-phenyl; S(0)n-alkyl; S (0)n-alkylphenyl and morpholino radicals; all the alkyl and phenyl radicals being themselves optionally substituted with one or more radicals , which may be identical or different, chosen from hal
  • R2 and R2' which may be identical or different, are chosen from hydrogen and alkyl optionally substituted with aryl or heteroaryl themselves optionally substituted by one or more radicals chosen among halogen, alkyl, OH or alcoxy;
  • A represents CH2
  • B represents a quinolyl, pyrimidinyle or pyridyl radical optionally substituted by one or more radicals identical or different chosen among halogen; -NH2;
  • R2 and R2' which may be identical or different, can be chosen from hydrogen and alkyl optionally substituted with benzothienyle.
  • B can represent a quinolyl, pyrimidinyle or pyridyl radical with pyrimidinyle optionally substituted by NH2 and pyridyl optionally substituted by halogen; -NH-CH2-CF3; - NH-CO-N (alk) 2; -NH-pyridyl; -NH-thiazolyl; -NH- pyrimidinyle and -NH-pyrazolyl optionally substituted by one or more radicals identical or different chosen among halogen, alkyl and alcoxy; phenyl and -NH-phenyl optionally substituted by one or more radicals identical or different chosen among alkyl, alcoxy, CO2H, CO2ethyl, N(alk) 2 (ex42) and CO-N(alk) 2; ⁇ NH-CO-phenyl and -NH-CO- pyridyl optionally substituted by one or more radicals identical
  • B represents a 4-quinolyl or 4- pyridyl radical optionally substituted with one or more radicals chosen from F, Cl, OH, CH3, CH2CH3, 0CH3, NH2, NHAIk and N (alk) 2, and phenyl, NH-phenyl; NH-heteroaryl NH-CO-phenyl, NH-CO-heteroaryl; NH-CO-NH-alkyl; NH-CO-NH- dialkyl the alkyl and phenyl radicals being themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl and alkoxy radicals.
  • B represents 4-pyridyl and 4-quinolyl radicals substituted with one or two radicals chosen from F, Cl, OH ; NH2 and OCH3.
  • a subject of the present invention is especially the products of formula (I) as defined above in which V is chosen from all the values defined above, R2 and R2' , which may be identical or different, are chosen from hydrogen and alkyl;
  • A represents CH2
  • B represents a quinolyl or pyridyl radical; the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I) .
  • a subject of the present invention is, most particularly,. the products of formula (I) as defined above in which V represents pyridine; pyrimidine; pyrrole; thiophene; thiazole; imidazole; oxazole; pyrazole; isoxaozole; ; indazole; benzimidazole; benzothiazole; benzoxazole; 2,3- dihydro-lH-indole; 2, 3-dihydro-lH-isoindole; 2,3- dihydrobenzothiazole; triazole; oxadiazole; dihydrobenzothiazine; benzodioxinyl; benzopyranyl; quinolyl;
  • Y and Yl which may be identical or different, are such that one from among Y and Yl is chosen from alkyl, optionally substituted by one or more fluorine atoms, phenyl, 0-phenyl, S(O)n-alkyl, S (0) n-alkylphenyl and morpholino and one or and the other from among Y and Yl is chosen from these same values and in addition from the following values: F, Cl and Br atoms; hydroxyl; oxo; cyano; free or esterified carboxyl; COCH3; phenyl; 0- phenyl; S(0)n alkyl; S (0) n-alkylphenyl and morpholino radicals; all the alkyl and phenyl radicals being themselves optionally substituted with one or more radicals , which may be identical or different, chosen from halogen atoms and alkyl, alkoxy, 0CF3, cyano, amino, alkylamino and dial
  • R2 and R2' which may be identical or different, are chosen from hydrogen and alkyl;
  • A represents CH2
  • B represents a quinolyl or pyridyl radical; the said products of formula (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, and also the addition salts with mineral and organic acids or with mineral and organic bases of the said products of formula (I) .
  • V represents pyridine; pyrimidine; pyrrole; thiophene; thiazole; imidazole; oxazole; pyrazole; isoxaozole; ; indazole; benzimidazole; benzothiazole; benzoxazole 2, 3-dihydro-lH-indole; 2,3- dihydro-lH-isoindole; 2, 3-dihydrobenzothiazole; all these radicals being optionally substituted as indicated above.
  • V represents 2, 3-dihydro-lH-indole and pyrazole.
  • the compounds of the general formula I can be prepared by initially converting a heterocyclic amino compound of the general formula 1 in which Y' and Yl' have the meanings stated for Y and Yl
  • These reactive derivatives are prepared in an inert organic solvent such as, for example, toluene, 1,2- dichloroethane or THF, at a temperature between -20 0 C and the reflux temperature of the particular solvent.
  • Preferred solvents are toluene and 1,2-dichlorethane, and preferred reaction temperatures are from -20 to +5 0 C. during the addition and reflux temperature for completion ' of the reaction.
  • the reaction can be assisted by addition of a base, but is preferably carried out without addition of base. .
  • the reactive derivatives of the general formula 2 can be isolated, but the intermediates are preferably used without further purification, where appropriate after replacement of the solvent, directly for f ⁇ rther reaction.
  • Reaction of the intermediates with a structural unit of the general formula 4 in which Z is COOR or CN is carried out in an inert organic solvent such as, for example, toluene, chlorobenzene, THF, dioxane or ethyl acetate, at a temperature between room temperature and the reflux temperature of the solvent.
  • the reaction can be assisted by addition of a base such as, for example, triethylamine or potassium tert-butoxide, ' but is preferably carried out without addition of base.
  • the initial linkage of the reactive intermediates 2 or 3 with the amino derivative of the general formula 4 and the subsequent ring closure to form the central heterocycle is preferably carried out in one step.
  • reaction of the structural unit 4 with carbonyldiimidazole, phosgene, diphosgene or triphosgene to give a reactive intermediate.
  • the reaction is preferably carried out with carbonyldiimidazole in an inert organic solvent such as, for example, toluene, 1,2- dichloroethane or THF at a temperature between -20 0 C and RT.
  • THF is the particularly preferred solvent.
  • the intermediates such as, for example, the derivatives of the general formula 6 (from reaction of 4 with carbonyldiimidazole) are then reacted in a solvent such as, for example, DMF, toluene, 1, 2-dichloroethane or THF with a heterocyclic amino compound of the general formula 1.
  • a solvent such as, for example, DMF, toluene, 1, 2-dichloroethane or THF
  • the reaction is preferably carried out at a temperature between RT and the boiling point of the solvent.
  • Open-chain intermediates are preferably cyclized directly to compounds of the general formula Ia and b, which can be converted by further derivatization reactions known to the skilled worker into compounds of the general formula I.
  • the compounds of the general formula Ia can additionally be obtained by reacting compounds of the general formulae 2 and 3 with a structural unit of the general formula 7 .
  • the reactions are preferably carried out in an organic solvent such as, for example, dimethylformamide, N- methylpyrrolidone, ethyl acetate or acetone in the presence of a base such as, for example, potassium carbonate, caesium carbonate, sodium hydride or potassium tert-butoxide.
  • a base such as, for example, potassium carbonate, caesium carbonate, sodium hydride or potassium tert-butoxide.
  • Dimethylformamide and caesium carbonate are preferably used.
  • some intermediates compounds or some compounds of formula (I) may be transformed to obtain some (or other) compounds of formula (I) and for that, to obtain products or other products of formula (I) , these products may be subjected if desired, and necessary, to one or more of the following conversion reactions, in any order: a) a reaction for esterification of an acid function, b) a reaction for saponification of an ester function to an acid function, c) a reaction for oxidation of- ' an alkylthio group to the corresponding sulfoxide or sulfone group, d) a reaction • for conversion of a ketone function to an oxime function, e) a reaction for reducing a free or esterified carboxyl function to an alcohol function, f) a reaction for conversion of an alkoxy function to a hydroxyl function, or alternatively of a hydroxyl function to an alkoxy function, g) a reaction for oxidation
  • hydroxyl groups may be protected, for example, with alkyl radicals such as tert-butyl, trimethylsilyl, tert- butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
  • alkyl radicals such as tert-butyl, trimethylsilyl, tert- butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl
  • amino groups may be protected, for example, with acetyl, trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, phthalimido radicals or other radicals known in peptide chemistry,
  • acyl groups such as the. formyl group may be protected, for example, in the form of cyclic .or noncyclic ketals or thioketals such as dimethyl or diethylketal or ethylene dioxyketal, or diethylthioketal or ethylenedithioketal,
  • the acid functions of the products described above may be, if desired, amidated with a primary or secondary amine, for example in methylene chloride in the presence, for example, of l-ethyl-3- (dimethylaminopropyl) carbo- diimide hydrochloride at room temperature,
  • the acid functions may be protected, for example, in the form of esters formed with readily cleavable esters such as benzyl esters or tert-butyl esters, or esters known in peptide chemistry.
  • esters formed with readily cleavable esters such as benzyl esters or tert-butyl esters, or esters known in peptide chemistry.
  • These reactions a) to k) indicated above may be performed, for example, as indicated below.
  • the products described above may, if desired, undergo, on the possible carboxyl functions, esterification reactions that may be performed according to the usual methods known to those skilled in the art.
  • ester functions into an acid function of the products described above may be, if desired, performed under the usual conditions known to those skilled in the art, especially by acid or alkaline hydrolysis, for example with sodium hydroxide or potassium hydroxide in alcoholic medium such as, for example, in methanol, or alternatively with hydrochloric acid or sulfuric acid.
  • acid or alkaline hydrolysis for example with sodium hydroxide or potassium hydroxide in alcoholic medium such as, for example, in methanol, or alternatively with hydrochloric acid or sulfuric acid.
  • alkylthio groups in the products described above in which the alkyl radical is optionally substituted with one or more halogen atoms, especially fluorine, may, if desired, be converted into the corresponding sulfoxide or sulfone functions under the usual conditions known to those skilled in the art such as, for example, with peracids such as, for example, peracetic acid or meta-chloroperbenzoic acid, or alternatively with ozone, oxone or sodium periodate in a solvent such as, for example/ methylene chloride or dioxane at room temperature.
  • the production of the sulfoxide function may be promoted with an equimolar mixture of the product containing an alkylthio group and the reagent such as, especially, a peracid.
  • the production of the sulfone function may be promoted with a mixture of the product containing an alkylthio group with an excess of the reagent such as, especially, a peracid.
  • the reaction for. conversion of a ketone function into an oxime may be performed under the usual conditions known to those skilled in the art, such as, especially, a reaction in the presence of an optionally O-substituted hydroxylamine in an alcohol such as, for example, ethanol, at room temperature or with heating.
  • the possible free or esterified carboxyl functions of the products .described above may be, if desired, reduced to an alcohol function by the methods known to those skilled in the art: the possible esterified carboxyl functions may be, if desired, reduced to an alcohol function by the methods known to those skilled in the art and especially with lithium aluminum hydride in a solvent _ such as, for example, tetrahydrofuran or dioxane. or ethyl ether.
  • the possible free carboxyl functions of the products described above may be, if desired, reduced to an alcohol function especially with boron hydride.
  • the possible alcohol functions of the products described above may be, if desired, converted into an aldehyde or acid function by oxidation under the usual conditions known to those skilled in the art, such as, for example, by the action of manganese oxide to obtain the aldehydes, or of Jones' reagent to access the acids, h)
  • the possible nitrile functions of the products described above may be, if desired, converted into tetrazolyl under the usual conditions known to those skilled in the art, such as, for example, by cycloaddition of a metal azide such as, for example, sodium azide or a trialkyltin azide on the nitrile function, as indicated in the method described in the article referenced as follows:
  • reaction for conversion of .a carbamate into urea and especially of a sulfonylcarbamate into sulfonylurea may be performed, for example, at the reflux point of a solvent such as, for example, toluene, in the presence of the appropriate amine.
  • the possible optically active forms of the products described above may be prepared by resolving the racemic mixtures according to the- usual methods known to those skilled in the art.
  • the possible reactive functions are hydroxyl or amino functions.
  • Usual protecting groups are used to protect these functions. Examples that may be mentioned include the following protecting groups for the amino radical: tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl, benzyloxycarbonyl.
  • Protecting groups for the hydroxyl radical include radicals such as formyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl and tert- butyldimethylsilyl. It is clearly understood that the above list is not limiting and that other protecting groups, which are known, for example, in peptide chemistry, may be used. A list of such protecting groups ' is found, for example, in French ⁇ patent 2 499 995,- the content of which is incorporated herein by reference. The possible reactions for removal of the protecting groups are performed as indicated in said patent 2 499 995.
  • the preferred method of removal is acid hydrolysis with acids chosen from hydrochloric acid, benzenesulfonic acid or para-toluene.sulfonic acid, formic acid or trifluoroacetic acid.
  • Hydrochloric acid is preferred.
  • •pyridine may be used, for example.
  • the possible esterification or salification of a COOH group is performed under the standard conditions known to those skilled in the art.
  • a primary or secondary amine may be used on a functional derivative of the acid, for example a symmetrical or mixed anhydride.
  • the products of formula (I) according to the present invention may be prepared by application or adaptation of known methods and especially of the methods described in the literature such as, for example, those described by R.C. Larock in: • Comprehensive Organic Transformations, VCH publishers, 1989.
  • the heterocyclic amino compounds of the general formula 1 are in some cases commercially available or are described in the literature or can be obtained from derivatives disclosed in the literature by transformations known to a person skilled in the art.
  • the precursors 4 can be obtained for example by reductive amination of aldehydes of the general formula OHC-A" -B' -Y 2 ' , which are commercially available or are prepared by conventional processes, with amino acid derivatives or amino nitriles of the general formula 7.
  • the products of the present invention are endowed with, advantageous pharmacological properties: it has been found that they especially have inhibitory properties on protein kinases
  • IGFlR insulin growth factor receptor
  • the products of formula (I) may also be used in the veterinary field.
  • a subject of the invention is thus the use, as medicinal products, of the pharmaceutically acceptable products of general formula (I) .
  • a subject of the invention is particularly the use, as medicinal products, of the products, the names of which are given hereinbelow: - 3- (5-Isopropyl-thiazol-2-yl) -5, 5-dimethyl-l-quinolin-4- ylmethyl-imidazolidine-2, 4- dione
  • a subject of the invention is particularly the use, as medicinal products, of the products, the names of which are given hereinbelow:
  • the products may be administered via the parenteral, buccal, perlingual, rectal or topical route.
  • a subject of the invention is also pharmaceutical compositions, characterized in that they contain, as active principle, at least one of the medicinal products of general formula (I) .
  • compositions may be in the form of injectable solutions or suspensions, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions.
  • These pharmaceutical forms are prepared according to the usual methods .
  • the active principle may be incorporated into excipients usually used in these compositions, such as aqueous or nonaqueous vehicles, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, fatty substances of animal or plant origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, and preserving agents.
  • the usual dose which varies according to the individual treated and the complaint under consideration, may be, for example, from 10 mg to 500 mg per day orally in man.
  • the present invention thus relates to the use of products of- formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of medicinal products for inhibiting the activity of protein kinases and especially of a protein kinase.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is a protein tyrosine kinase.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is chosen from the following group:
  • Such protein kinase is chosen more especially from the following group: IGFl, cdc7, Auroral-2, Src, Jnk, FAK, KDR, IR, Tie2, CDK7, CDK2 et EGFR.
  • the present invention thus relates particularly to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in whioh the protein kinase is IGFlR.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is FAK.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is AKT.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) in which the protein kinase is in a cell culture, and also to this use in a mammal.
  • the present invention thus relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicinal product for preventing or treating a disease characterized by deregulation of the activity of a protein kinase and especially such a disease in a mammal.
  • the present invention relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicinal product for preventing or treating a disease belonging to the following group: disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, acromegaly, metabolic disorders, allergies, asthma, Crohn's disease, thrombosis, diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, aging, age related macula degeneration, oncology diseases and cancer.
  • a disease belonging to the following group: disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, acromegaly, metabolic disorders, allergies, asthma, Crohn's disease, thrombosis, diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, aging, age related mac
  • the present invention thus relates to the use of products of formula (I) - as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicinal product for treating oncology diseases.
  • the present invention relates particularly to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicinal product for treating cancers.
  • the present invention is most particularly of interest in the treatment of solid tumours and the treatment of cancers that are resistant to cytotoxic agents.
  • the present invention relates most particularly to the treatment of breast cancer, stomach cancer, cancer of the colon, lung cancer, cancer of the ovaries, cancer of the uterus, brain cancer, cancer of the kidney, cancer of the larynx, cancer of the lymphatic system, cancer of the thyroid, cancer of the urogenital tract, cancer of the tract including the seminal vesicle and prostate, bone cancer, cancer of the pancreas and melanomas.
  • the present invention is even more particularly of interest in treating breast cancer, cancer of the colon and lung cancer.
  • the present invention also relates to the use of products of formula (I) as defined above or of pharmaceutically acceptable salts of said products of formula (I) for the preparation of a medicinal product for cancer chemotherapy.
  • the products of formula (I) according to the present invention may be used alone or in combination with chemotherapy or radiotherapy or alternatively in combination with other therapeutic agents .
  • the present invention thus relates especially to the pharmaceutical compositions as defined above, also containing active principles of other chemotherapy medicinal products for combating cancer.
  • Such therapeutic agents may be commonly used antitumour agents.
  • inhibitors of protein kinases mention may be made especially of butyrolactone, flavopiridol, 2- (2-hydroxyethylamino) -6-benzylamino-9- ' methylpurine, olomucine, Glivec and Iressa.
  • the products of formula (I) according to the present invention may thus also be advantageously used in combination with antiproliferative agents: as examples of such antiproliferative agents, but without, however, being limited to this list, mention may be made of aromatase inhibitors, antiestrogens, the topoisomerase I inhibitors, the topoisomerase II inhibitors, microtubule- active agents, alkylating agents, histone deacetylase inhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that reduce the activity of protein kinases and also anti-angiogenic compounds, gonadorelin agonists, antiandrogens, bengamides, biphosphonates and trastuzumab.
  • antiproliferative agents examples of such antiproliferative agents, but without, however, being limited to this list, mention may be made of aromatase inhibitors, antiestrogens, the
  • anti- microtubule agents for instance taxoids, vinca alkaloids, alkylating agents such as cyclophosphamide, DNA-intercalating agents, for instance cis-platinum, agents that are interactive on topoisomerase, for instance camptothecin and derivatives, anthracyclines, for instance adriamycin, antimetabolites, for instance 5-fluorouracil and derivatives, and the like.
  • anti- microtubule agents for instance taxoids, vinca alkaloids, alkylating agents such as cyclophosphamide, DNA-intercalating agents, for instance cis-platinum, agents that are interactive on topoisomerase, for instance camptothecin and derivatives, anthracyclines, for instance adriamycin, antimetabolites, for instance 5-fluorouracil and derivatives, and the like.
  • the present invention thus relates to products of formula
  • the present invention relates particularly to products of formula (I) as defined above as IGFlR inhibitors.
  • the present invention also relates to products of formula (I) as defined above as FAK inhibitors.
  • the present invention also relates to products of formula (I) as defined above as AKT inhibitors.
  • the present invention relates more particularly to the products of formula (IA) as defined above as IGFlR inhibitors.
  • Example 1 5-Isopropyl-3- (4-phenyl-thiazol-2-yl) -1- pyridin-4-ylmethyl-imidazolidine-2, 4- dione 550 mg (2,8mmol) diphosgene in 20ml 1, 2-dichlorethane were treated at -20 0 C with a solution of 198mg (l,lmmol) 2-amino-4-phenylthiazole in 20 ml 1, 2-dichlorethane. The mixture was allowed to come to room temperature and then was refuxed for 5h. The solvent was evaporated and the residual oil was taken up in 40ml THF.
  • Example 2 5-Isopropyl-3- (5-phenyl-pyridin-2-yl) -1- pyridin-4-ylmethyl-imidazolidine-2, 4- dione
  • This product was prepared according to the procedure described for example 1 using l.lg (5.6mmol) diphosgene, 383mg (2..25mmol) 5-pheny.l-pyridin ⁇ 2-ylamine and 500mg (2.25mmol) .3-methyl-2- [ (pyridin-4-ylmethyl) -amino] - butyric acid methyl ester.
  • Example 4 5-Isopropyl-3- (l-methyl-lH-indazol-5-yl) -1- pyridin-4-ylmethyl-imidazolidine-2, 4-dione; compound with trifluoro-acetic acid ⁇ l ⁇ mg (3.8mmol) carbonyldiimidazole and 31 mg (0.45mmol) imidazole in 8ml- THF were treated at 0°C with 462. lmg (3.14mmol) ' l-methyl-lH-indazol-6-ylamine in 10 ml THF and stirred for Ih.
  • Example 7 3- (5-Bromo-pyridin-2-yl) -5, 5-dimethyl-l- pyridin-4-ylmethyl-imidazolidine-2, 4-dione; compound with trifluoro-acetic acid
  • Example 8 5, 5-Dimethyl-3- (4-phenyl-thiazol-2-yl) -1- pyridin-4-ylmethyl-imidazolidine-2, 4-dione; compound with trifluoro-acetic acid
  • Example 9 5, 5-Dimethyl-3- (2-oxo-4-trifluoromethyl-2H-l- benzopyran-7-yl) -l-pyridin-4-ylmethyl-imidazolidine-2, 4- dione trifluoroacetate 5,1 g (25 iranol) 2-methyl-2- [ (pyridin-4-ylmethyl) -amino]- propionic acid methyl ester were dissolved in 102 ml tetrahydrofurane and treated at O 0 C with 4.46 g (27.5 mmol) carbonyldiimidazole. The mixture was stirred for 15 min at O 0 C and Ih at RT.
  • Example 11 5, 5-Dimethyl-3- (5-phenoxy-lH-benzimidazol-2- yl) -l-pyridin-4-ylmethyl-imidazolidine-2, 4-dione trifluoroacetate
  • Example 12 5, 5-Dimethyl-l-pyridin-4-ylmethyl-3- quinolin-3-yl ⁇ imidazolidine-2, 4-dione trifluoroacetate This product was prepared according to the procedure described for example 9 using 72mg 3-aminoquinoline. Yield : 32.2mg
  • Example 13 3- [5- (2-Chloro-6-fluoro-benzylsulfanyl) -2H- 1,2, 4-triazol-3-yl] -5, 5 ⁇ dimethyl-l-pyridin-4-ylmethyl- imidazolidine-2, 4-dione trifluoroacetate
  • Example 14 5, 5-Dimethyl ⁇ 3- (5-morpholin-4-yl-4H-l, 2, 4- triazol-3-yl) -l-pyridin-4-ylmethyl-imidazolidine-2, 4- dione trifluoroacetate
  • This product was prepared according to the procedure described for example 9 using 84.6mg 3-amino-5- morpholino-1, 2, 4-triazole.
  • Example 15 5, 5 ⁇ Dimethyl-3- (5-morpholin-4-yl-l / 3, 4- oxadiazol-2-yl) -l-pyridin ⁇ -ylmethyl-imidazolidine- ⁇ , 4- dione trifluoroacetate
  • Example 16 3- (2, 2-Dimethyl-4-oxo-4H-l, 3-benzodioxin-7- yl) -5, 5-dimethyl-l-pyridin-4-ylmethyl-imidazolidine-2, 4- dione trifluoroacetate
  • Example 17 5, 5-Dimethyl-3- (4-methyl-thiazol-2-yl) -1- quinolin-4-ylmethyl-imidazolidine-2, 4- dione
  • a solution of 344 mg di-imidazol-1-yl-methanone and 18 mg imidazole in 6 ml tetrahydrofuran a solution of 300 mg 2-amino-4-methyl-thiazole in 1 ml tetrahydrofuran was slowly added at O 0 C. After stirring at 0 0 C for 1 hour 320mg 2-methyl-2- [ (quinolin-4-ylmethyl) -amino] -propionic acid methyl ester were added and the reaction mixture was allowed to warm up to room temperature.
  • Example 18 5, 5-Dimethyl-l-quinolin-4-ylmethyl-3- (4- tri ' fluoromethyl-thiazol-2-yl) -imidazolidine-2, 4- dione
  • This compound was . prepared in analogy to example 17 by using 300 mg of the corresponding heteroarylamine instead of 2-amino-4-methyl-thiazole. Yield : 45mg MS (ES+) : m/e - 421
  • Example 19 3- (4-tert-Butyl-thiazol-2-yl) -5, 5-dimethyl- l-quinolin-4-ylmethyl-imidazolidine-2, 4- dione
  • Example 21 3- (5-Isopropyl-thiazol-2-yl) -5, 5 ⁇ dimethyl-l- quinolin-4-ylmethyl-imidazolidine-2, 4- dione
  • This compound " -was - prepared- in ⁇ ' •analogy to example 17 by using- 300 m ' g of -the corresponding heteroarylamine instead of 2-amino- : 4-methyl-thiazole.
  • 2-Amino-isopropyl-l, 3- thiaz-ole was prepared according ⁇ -to ' a procedure published .by ' Paolo Pevarello et al. , US Patent Application 2003134836. Yield: 204 mg MS(ES+) :.
  • the ' following compound was prepared in analogy to example- 17 by ⁇ using- .300' itig 5 ⁇ cyGlopro.pyl-2-methyl-2H-pyrazol-3-- ylamine . instead of ⁇ ' 2 ' -amino-4-methyl ⁇ thiazole'.. '
  • Example -25 3- (l-Acetyl-2, 3-dihydro-lH-indol-5-yl) -5, 5- dimethyl—l-quinolin-4-ylmethyl-imidazolidine- 2, 4-dione a) ⁇ 1- (5-amino-2, 3-dihydro-indol-l-yl) -ethanone was by ⁇ catalytic reduction of N-acetyl-5-nitroindole . as . described in example 24. b) The title compound was prepared in analogy to example 17 by using 160 mg 1- (5-amino-2, 3-dihydro-indol-l-yl) - ' ethanone. as starting material.
  • Step , D 0,317-.mmol . of the, hyda ⁇ toi ⁇ e from step C and 0,634 mmol ⁇ of 2-chloro-4-chloromethyl ⁇ pyridine are dissolved.in 5 ml of DMF and. after the addition 'of 1,427 mmol of Cs2CO3. the- resulting mixture is heated.: .to reflux for 3 h. After • evaporation ' of the .solvent the residue is subjected to chromatography on silica gel using a heptane-ethylacete. gradient.
  • Step _ 1 E
  • Step F 0,3.9 mmol of. the product, of step 4 and 0,43;mmol of the .. corresponding acid,are dissolved in 5 ml of DMF, 0, . 09rnmol- of Pd(PPh3)4 and 0,9 ml of IN Na2CO3 are added and . the . ' ⁇ resulting mixture is heated to 1OQ 0 C until completion, .of embrace the ⁇ reaction . (monitored ⁇ by . TLC) The '- ' solvent -is evaporated ' • and ' the residue subjected to,-
  • Example 34 25-. ⁇ 3- ⁇ 4-[3-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol- ⁇ - yl) -5, 5-dimethyl-2, 4-dioxo- imidazolidin-1-ylmethyl] - pyridin-2-yl ⁇ -l, 1-dimethyl-urea
  • step A ' and ' using , steps, B, C, D and E 30 with N,N-dimethylurea . • . ' •
  • Example 41 • • • • • • - ⁇ ' 3-(l-Acetyl-3 f 3-dimeth : yl-2 : , 3-dihydro-lH-indol- ⁇ -yl) -1- [2- . • (2, 6-dimethoxy-pyrimidin-4- "" ylamino) -pyridin-4-ylmethyl] - ⁇ ' 5/5-dimet ' hyl-imidazolidine-2, 4-dione ⁇ . ., .-.• ⁇ ,
  • example. 40 50 mg are dissolved in 5 ml- of ethanol and -5 ml of HCl cone. Are added. The resulting mixture is heated to 5O 0 C and stirred ⁇ for 4 hours. The solvent is • evaporated- in vacuo and the product, collected.
  • Example 44 • N--f.4 ' -[ ' 3 ⁇ (l-Acetyl-3, 3-dimethyl : -2,-3-dihydro-lH-indol-6- . • ': - : yl) ' -5V-5-dimethyl-2. / .4-di ⁇ xo- ' ' ; - imidazolidin-1-ylme.thyl] -. • py-ridi ⁇ i- : 2-yl ⁇ -2-methoxy-isonicotinai ⁇ ide ⁇ ' . /.-..••
  • example 40 50 mg are dissolved in 5 ml of ethanol and 5 ml of HCl cone. Are added. The resulting mixture is heated to 5O 0 C and stirred for ' 4 hours. The solvent is evaporated in vacuo and the product collected.
  • Example 60 ⁇ ' ⁇ • ⁇ 4- ⁇ 4-[3-(3,3-Dimethyl-2,3-dihydro-lH-indol- ⁇ -yl)-5,5- dimethyl-2, 4-dioxo-imidazolidin-l- ylmethyl] -pyridin-2- yl ⁇ -N,N-dimethyl-b ' enzamide ⁇ ⁇
  • Example 62 3- ⁇ 4-[3-(l-Acetyl-3/3-dimethyl-2,3-dihydro-lH-indql-6- ,., yl)-5, 5-dimetHyl-2, 4-dioxo- ' ' ⁇ imidazolidin-1-ylmethyl] - ⁇ pyridin-2-ylamino ⁇ -N,N-d ⁇ methyl-benzamide
  • reaction mixture was treated with water.
  • the organic layer was dried over anhydrous sodium sulfate.
  • Example 74 3-(3,3-Dimethyl-2,3-dihydro-lH-indol-6-yl)-5,5-dimethyl-. l-pyrid ⁇ n-4-ylmethyl- imidazolidine ⁇ 2, 4-dione 45 mg 3- (l-acetyl-3, 3-dimethyl-2, 3-dihydro-lH-indol- ⁇ - yl) -5, 5-diinethyl-l-pyridin-4-ylmethyl- imidazolidine-2, 4- dione were dissolved in a mixture of 0.5 ml dioxane and 0.5 ml of an aqueous 1 N solution of hydrochloric acid in a process vial.
  • Example 75 ⁇ 1-- ( 2-Amirto-pyrimidin-4-ylmethyl) --3- ( 3 , 3 -dime thy 1-2 , 3-. dihydro-lH-indol- ⁇ -yl) -5 , 5- dimethyl-imidazolidine-2 , 4 ⁇ , dione . . . .
  • Example 7'6a ⁇ ⁇ l/3,3-Trimethyl-6-nitro ⁇ 2,3-dihydro-lH-indole To a solution of 400 mg 3, 3-dimethyl- ⁇ -nitro-2, 3-dihydro- IH-indole. in 4 ml N,N-dimethylformamide 350 mg potassium tert-butoxide and 443 mg iodomethane were added at 0 0 C. 0 After stirring for 1 hour the solvent was removed under reduced pressure. The residue was dissolved in a mixture of dichloro-methane and water. The organic layer was dried- " over- sodium sulfate and the solvent was removed under reduced pressure.
  • Example 78a " ⁇ ' 2- (2, 4-Dinitro-phenyl) -2-methyl-propionic acid ethyl ester - 5 '•
  • a solution of 1 g- 2-methyl-2-phenyl-propionic acid ethyl ester in a mixture of " 14 ml ' sulfuric acid and 1 ml nitric acid was stirred at room temperature for 4 hours.
  • the mixture was added to ice water and extracted with ethyl acetate.
  • the organic layer was washed with a satured 0 aqueous solution of sodium hydrogen carbonate and dried over ⁇ anhydrous sodium sulfate. Filtration and concentration of the solvent under reduced pressure yielded a yellow solid ; .
  • Example 80 5-Benzo [b]thiophen-3-ylmethyl-3 (lH-indaz.ol--5- ' 30 yl) -1-pyridin—4-ylmethyl-imidazolidine-2,'4-dione- • . ⁇ ,
  • the finished resin was washed-wifh- ' l- " x 10- ml ' of DCM, " : 3- . x ' 10 ml of DMF, 2 x .10 ml of - 1 DCM-,- •• 2 x 10 -ml- of methanol, 2 x 10 ml of. DCM and .2 -x ⁇ 10 : -ml- ' of- methanol.
  • The" resin was .dried under- vacuum prior to ' ' treatment with 6 ml of 95:5 TFA: H2.0. and 5 agitated for 24 hours. The resin ' was filtered out and washed with ' additional 5 ml of TFA: H20 mixture.
  • Excipient for a finished tablet weighing I g 5 (details of the excipient: lactose, talc, starch, ⁇ magnesium stearate).

Abstract

L'invention concerne les nouveaux produits de formule (I), dans laquelle V représente un radical hétérocyclique. Ces produits sont utilisés en tant qu'inhibiteurs des protéines kinases.
PCT/EP2005/008721 2004-07-27 2005-07-25 Derives d'uree cycliques substitues par des heterocycles, preparation et utilisation pharmaceutique de ces derives en tant qu'inhibiteurs de kinases WO2006010642A1 (fr)

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MX2007000735A MX2007000735A (es) 2004-07-27 2005-07-25 Derivados de urea ciclicos sustituidos con heterociclo, preparacion de los mismos y uso farmaceutico de los mismos como inhibidores de quinasa.
JP2007523039A JP2008508229A (ja) 2004-07-27 2005-07-25 複素環置換された環状尿素誘導体、その調製及びキナーゼ阻害剤としてのその薬学的使用
AU2005266461A AU2005266461A1 (en) 2004-07-27 2005-07-25 Heterocycle-substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
CA002571324A CA2571324A1 (fr) 2004-07-27 2005-07-25 Derives d'uree cycliques substitues par des heterocycles, preparation et utilisation pharmaceutique de ces derives en tant qu'inhibiteurs de kinases
BRPI0513863-9A BRPI0513863A (pt) 2004-07-27 2005-07-25 derivados de uréia cìclica substituìda por heterociclo, preparação dos mesmos e uso farmacêutico dos mesmos como inibidores de cinase
EP05776537A EP1773828A1 (fr) 2004-07-27 2005-07-25 Dérivées d'urée cyclique substitués par un heterocycle, leur prépration et leur utilisation pharmaceutique comee inhibiteurs de kinases
EA200700142A EA200700142A1 (ru) 2004-07-27 2005-07-25 Замещенные гетероциклом циклические производные мочевины, их получение и их фармацевтическое применение в качестве ингибиторов киназы
IL180257A IL180257A0 (en) 2004-07-27 2006-12-21 Heterocycle-substituted cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors
US11/627,505 US20070259891A1 (en) 2004-07-27 2007-01-26 Heterocycle-Substituted Cyclic Urea Derivatives, Preparation Thereof And Pharmaceutical Use Thereof As Kinase Inhibitors
NO20071073A NO20071073L (no) 2004-07-27 2007-02-26 Heterocykel-substituerte cykliske ureaderivater, fremstilling derav og farmasoytisk anvendelse derav som kinaseinhibitorer

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NO20071073L (no) 2007-04-26
SG140591A1 (en) 2008-03-28
US20070259891A1 (en) 2007-11-08
UY29037A1 (es) 2006-02-24
BRPI0513863A (pt) 2008-05-20
AU2005266461A1 (en) 2006-02-02
EA200700142A1 (ru) 2007-08-31
TW200617004A (en) 2006-06-01
MX2007000735A (es) 2007-03-30
CN1993359A (zh) 2007-07-04
PE20060556A1 (es) 2006-07-03
IL180257A0 (en) 2007-07-04
KR20070044440A (ko) 2007-04-27
ZA200700706B (en) 2008-10-29
MA28753B1 (fr) 2007-07-02
AR050267A1 (es) 2006-10-11

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